VIVO complexes with antibacterial quinolone ligands and their interaction with serum proteins

Daniele Sanna, Valeria Ugone, Giuseppe Sciortino, Péter Buglyó, Zsolt Bihari, Péter László Parajdi-Losonczi, Eugenio Garribba

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© 2018 The Royal Society of Chemistry. Quinolone derivatives are among the most commonly prescribed antibacterials in the world and could also attract interest as organic ligands in the design of metal complexes with potential pharmacological activity. In this study, five compounds, belonging to the first (nalidixic acid or Hnal), second (ciprofloxacin or Hcip, and norfloxacin or Hnor) and third generation (levofloxacin or Hlev, and sparfloxacin or Hspar) of quinolones, were used as ligands to bind the VIVO2+ ion. In aqueous solution, mono- and bis-chelated species were formed as a function of pH, with cis-[VOHxL2(H2O)]x+ and [VOHxL2]x+, x = 0-2, being the major complexes at pH 7.4. DFT calculations indicate that the most stable isomers are the octahedral OC-6-32 and the square pyramidal SPY-5-12, in equilibrium with each other. To the best of our knowledge, this is the first case that an equilibrium between a penta-coordinated square pyramidal complex and a hexa-coordinated octahedral complex is observed in solution for ligands forming six-membered chelated rings. Nalidixic acid forms the solid compound [VO(nal)2(H2O)], to which a cis-octahedral geometry was assigned. The interaction with 1-methylimidazole (MeIm) causes a shift of the equilibrium SPY-5 + H2O → OC-6 toward the right after the formation of cis-[VOHxL2(MeIm)]x+, where MeIm replaces an equatorial water ligand. The study of the systems containing [VO(nal)2(H2O)] and the serum proteins-albumin (HSA), apo-transferrin (apo-hTf) and holo-transferrin (holo-hTf)-indicates that HSA and holo-hTf form the mixed species {VO(nal)2}y(HSA) and {VO(nal)2}y(holo-hTf), where y = 1-3 denotes the number of VO(nal)2 moieties bound to accessible histidines (His105, His367, His510 for HSA, and His25, His349, His606 for holo-hTf), whereas apo-hTf yields VO(nal)2(apo-hTf) with the coordination of the His289 residue only. Docking calculations suggest that the specific conformation of apo-hTf and the steric hindrance of the cis-VO(nal)2 moiety interfere with its interaction with all the surface His residues and the formation of a hydrogen bond network which could stabilize the binding sites.
Original languageEnglish
Pages (from-to)2164-2182
JournalDalton Transactions
Issue number7
Publication statusPublished - 1 Jan 2018


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